Tolerance, Autoimmunity,

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Tolerance, Autoimmunity, Immunodeficiences
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Tolerance
Tolerance is broadly defined as a state of
unresponsiveness to an antigen, be it self or
foreign Antigen-specific cell receives signals
that either activate OR inactivate the
cell Central tolerance to self antigens is
acquired during development through the
elimination or silencing of lymphocytes capable
of binding self antigens Peripheral tolerance is
induced in mature lymphocytes in the periphery
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Mechanisms to induce tolerance Elimination of
self-reactive lymphocytes clonal
deletion (negative selective of T and B cells
during development) Silencing of self-reactive
lymphocytes clonal anergy
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Clonal deletion of self-reactive lymphocytes
occurs within primary lymphoid organs
T-cells - thymus
B-cells bone marrow
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• Clonal deletion can also occur in the periphery
• Mechanisms
• Fas FasL interactions apoptosis
• T suppressor/regulatory cells Treg, CD4CD25
• may kill by perforin/granzyme mechanism

Autoimmune diseases
CD4CD25- T cells
Athymic nude
No disease
CD4CD25- T cells CD4CD25 Treg
Athymic nude
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Clonal anergy of self-reactive lymphocytes can
also occur in the periphery
T cells
Tissue cell has no B7 No co-stimulation Anergy
Inactivation of the cell nonresponder
CD28
B cells can also be anergized in the absence of
co-stimulation, usually CD40-CD40L
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Other factors involved in Tolerance -Dose/Route
of Antigen -Inappropriate cytokine
responses -anti-idiotypic responses -Psychogenic
factors (poorly defined but could include the
immunosuppressive effect of steroid hormones)
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Tolerance to a fetus The fetus is really an
allograft with nonself MHC proteins RBCs of
the father so why is it not rejected by the
mother? We know mothers makes antibodies against
fathers MHC RBC
Potential mechanisms Placenta outer layer does
not express classical MHC proteins
expresses a molecule that inhibits NK cell
killing depletion of tryptophan
necessary T cell nutrient T cell tolerance to
paternal ags, suppressed T cell
responses Secretion of cytokines that suppress
TH1 cells IL4, IL10, TGFb Role for Treg cells?

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Immune privileged sites Eye Testis Brain Ovary
Placenta Potential reasons The presence of FasL
expressing cells that kill infiltrating
inflammatory T cells (Fas) Immunosuppressive
cytokines
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Autoimmunity
Autoimmunity constitutes immune response against
self antigen. Autoimmunity may be benign or may
be damaging to host An immune response against
self antigen(s) that results in the destruction
of host tissue or damage to the function of an
organ or tissue constitutes autoimmune disease
Autoimmunity can be thought of as a breakdown of
tolerance, which is multi-layered, consisting of
both central and peripheral mechanisms
Occasionally, self-reactive cells escape,
resulting in autoimmune diseases (approximately
5 U.S. population)
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Autoimmune diseases are multifactorial genetic
environment
Contributing factors

• Genetics. Presentation of self-antigens by MHC
  molecules
• Linkage to certain MHC alleles in many autoimmune
  diseases

• Initiating Event
• Environmental Chemical exposure
• Infection Viral and bacterial infection
• molecular mimicry-cross reactivity between a
• microbial antigen with a self-antigen

• Autoreactive lymphocytes

• Gender Females more frequently affected

• Handedness a tenuous but statistically-signific
  ant
• higher frequency in left-handed people

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Bacterial infections can lead to immune-mediated
pathology
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Classification of autoimmune disease Historically
organ or systemic Effector mechanism
antibody, complement, T cells
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Antibody mediated diseases Autoimmune hemolytic
anemia destruction of RBCs Myasthenia Gravis
autoab to acetylcholine receptor, inhibits
nerve impulse transmission (blocking ab) Graves
disease autoab to receptor for
thyroid- stimulating hormone, activates cell to
release thyroid hormone (activating
ab) Systemic Lupus Erythematosus - wide spectrum
of autoreactive antibodies, anti-nuclear
antibodies against DNA,RNA, or nucleoproteins
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Systemic Lupus Erythematosus
Characteristic butterfly rash Damage to several
organs Kidney immune complex deposition can
lead to activation of C, inflammation Kidney
damage causes the most mortality in
SLE Trigger unknown
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T cell mediated diseases Multiple Sclerosis
demyelinization of CNS tissue T cell response to
myelin Type 1 Insulin-Dependent Diabetes
Mellitus Cytotoxic T cells to pancreatic
b-islet cells Hashimotos Thyroiditis -
anti-thyroglobulin T/B-cells Rheumatoid
Arthritis chronically inflamed
synovium activated T cells, macrophages, B
cells inflammatory cytokines TNF-a, IL-1
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Murine model of MS
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Rheumatoid Arthritis Immunotherapy with anti-TNF
a antibodies
Anti-IL-1bR antagonist to block action of IL-1b
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Immunodeficiencies
Immunodeficiencies when one or more component
of the immune system is defective

• Inherited immunodeficiences (genetic) are the
  most common
• IgA deficiency the most common of these (1 in
  800)
• The rest are rare (1 in 10,000)

• Acquired immunodeficiency
• - caused by malnutrition, seen in infants and
  children
• - caused by drugs or irradiation
• caused by viral infection, seen in patients of
  all ages
• alcoholism

• age very young or very old are
  immunodeficient

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• Genetic defects may affect components of
• innate immune system phagocytic cells,
  complement
• adaptive immune system T cells, B cells
• defects that affect CD4 T cells or the
  developmental stages of T and B cells severely
  compromise immune function. These are referred
  to as Severe Combined Immunodeficiency Disease
  (SCID)
• both innate and adaptive immune systems
• multiple defects that affect both arms of the
  immune system also result in severe compromise of
  immune functions. These are rare.

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Immunodeficiency Is often recognized by
recurrent infections The type of infection
depends on which component of the immune system
is compromised
Deficiency Disease___________________ B cell
Recurrent bacterial infections T
cell Susceptibility to viruses, fungi,
protozoans T B cell Infections with bacteria,
viruses, fungi, protozoans Phagocytic
cells Systemic infections with bacteria
that are of low virulence Complement Bacteria
l infections
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Defects in the innate arm of the immune system
Defective Genes/Proteins
Cells Affected
Decreased resistance to
Leukocyte Adhesion Molecules
Pyogenic (pus forming) bacteria
Phagocytes
Enzymes involved in intracellular killing
Intracellular Extracellular microbes
Phagocytes
Pyogenic (pus forming) bacteria and Neisseria
Complement
Not Applicable
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Defects in the adaptive arm of the immune system
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Generalized defects of the adaptive immune system
Note g chain is shared by receptors for IL2,
IL4, IL7, IL9 and IL15
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Acquired Immunodeficiencies Severe
immunodeficiency caused by HIV (AIDS) generalized
immunosuppression due to loss of CD4 T cells.
Immune suppression induced by Epstein-Barr
Virus (EBV) following infectious mononucleosis.
Radiation or Cytotoxic drugs Malnutrition Alco
holism
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Measuring Immune Responses to determine
immunodeficiency

• Innate Immunity ELISA for complement components,
• Cytotoxicity/Phagocytosis assays
• Humoral Immunity ELISA for antibody (total and
  specific)
• enumerate B-cells
• proliferative capacity
• Cellular Immunity Th- skin testing (DTH or
  Mantoux test),
• proliferation, cytokine production by ELISA,
• enumerate CD4 T-cells
• Tc- Cytotoxicity testing, IFN-g production,
• enumerate CD8 T-cells